Genetic screening of inherited predisposition to breast and ovarian cancer

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New DNA sequencing technologies that have showed great promise in the research community are now beginning to emerge in clinical use. Naturally designed to offer immense capacity and high sensitivity, these systems are well timed to address increasing demand and improve patient care. Over the last decade, we have witnessed significant increases in genetic testing, in both the volume and the types of test requests. Our lab at the Centre for Clinical Diagnostic Genomics (CDG) is now examining these new methods to determine how to best meet this demand.

Thanks to strategic funding from Genome BC and the Provincial Health Services Authority, the CDG recently implemented its first clinical offering of a “Next Generation” sequencing technology, which replaces traditional methods for genetic screening of inherited predisposition to breast and ovarian cancer (BRCA1 and BRCA2 genes). This implementation involved assessing the Next Generation sequencing in parallel with established methodologies, confirming method concordance and developing an understanding of key differences in the two methodologies. Not only were we able to successfully reproduce previous results, the higher resolution of the new technology provides a distinct advantage above and beyond traditional technologies. Previous sequencing technologies were able to detect variants present at ~20% in a sample, limiting their application to detection of inherited mutations or acquired mutations present at significant levels in the patient sample. Next Generation sequencing technologies are now capable of detection to ~1% levels. This greatly improved analytical sensitivity makes more disease conditions amenable to interrogation by sequencing methods.

Immediately upon implementing this technology, our laboratory was able to support a fourfold increase in demand with no significant correlating increase in wet lab resources. With traditional technologies, demand had slightly outpaced capacity, leading to pre-analytical waiting periods. Our increased capacity reverses this trend and will lead to minimizing overall test times.

While the ultimate goal of Next Generation technologies was to create a platform that could provide a “$1,000 genome” the utility of genome sequences in clinical practice has met resistance, in part due to concerns about incidental findings. Our initial offering of this technology replaced an existing test and thus did not face the concerns about incidental findings. This step did however allow us to become familiar with the method in clinical application and start to take advantage of capacity and cost benefits immediately. Taking advantage of the power of Next Generation sequencing to effectively scale in the number of gene targets analyzed at one time is the next logical step. “Gene Panels” representing all relevant targets in a particular disease are a natural extension of this methodology. With a disease panel approach, we can rapidly generate many relevant answers, while still avoiding the major pitfall of incidental findings associated with broader testing approaches such as whole genome sequencing.

One of our ongoing development efforts, which we hope to implement in 2013, is geared towards offering a panel approach of 14 genes related to predisposition in breast, ovarian and colorectal cancer. All 14 genes of the proposed panel may be investigated as part of the current standard of care, however they are done in a serial progression with incremental costs for each gene tested until an informative result is found or further testing costs become prohibitive. One significant advantage is that this panel approach would replace serial testing progression of candidate genes, alleviating the patient stress associated with repeated cycles of results anticipation.

Next Generation sequencing is a versatile tool that has demonstrated strong applicability, first in cancer research and now in patient care. Disease conditions beyond cancer are equally amenable to investigation using Next Generation sequencing. We are currently investigating applications to replace traditional testing and offer new tests for both cancer and non-cancer conditions